Diabetes markedly raises the risk of microvascular and macrovascular diseases, major contributors to higher morbidity and mortality in this increasingly prevalent disorder. The resulting poor tissue oxygenation due to compromised circulation accounts for the poor healing, infection, and deterioration of foot ulcers in diabetics; this is the basic underlying pathophysiological factor. In current clinical practice, there is no technique available for direct determination of tissue oxygen content. Instead, clinicians need to rely on various methods that attempt to measure perfusion such as Doppler ultrasound, or an indirect measure of tissue oxygenation, transcutaneous oxygen measurement (TcO2). The latter detects oxygen diffusing through skin warmed to 42-44? C by the instrument, which has a complex relationship to the actual pO2 in the tissue. This project will apply 2 emerging techniques; electron paramagnetic resonance (EPR) oximetry and near infrared spectroscopy (NIR) to measure tissue oxygenation more directly and reliably in healthy volunteers. The ultimate aim is to extend the techniques to diabetic patients for clinical management of the disease. EPR is a new oximetry modality that directly measures tissue oxygen content and NIR oximetry characterizes the amount and saturation of intravascular hemoglobin, so a combination of these 2 techniques will provide complementary information about oxygen delivery and local concentration, providing a more complete picture of the tissue oxygenation. The major potential advantages of EPR and NIR are that they provide information not previously available, namely direct tissue oxygen content, and that meaningful repeated measurements can be obtained non-invasively over a long period of time. This information would be extremely useful for characterizing the status of the disease, and to determine the effects of therapeutic intervention on tissue oxygenation, and the relationship between oxygenation and progression of the disease. Promising preliminary results have been obtained, indicating the feasibility of following tissue oxygen in humans for years. If the promise of these techniques is fulfilled, clinicians will have a new powerful tool for management of peripheral vascular disease, based on fundamental pathophysiology. [unreadable] [unreadable] [unreadable]